Studies concerning patients suffering from primary cancer outside the central nervous system (CNS) show that 20-25% of the patients develop metastasis of the CNS. However, the risk of developing metastases is dependent on the specific cancer form.
The metastatic complications are very often the patient's first symptom of cancer and may give rise to serious neurological complications at a time when the patient is unaffected by the primary cancer.
The treatment of primary cancer and metastasis of the CNS is far from satisfactory. Most measures, whether radiotherapy or chemotherapy, are limited by the fact that the treatment also affects the normal tissue; accordingly, the tolerance of the normal tissue to the specific treatment is of great importance. The most serious side-effect of chemotherapy is myelosuppression.
The target site for cytotoxic drugs differs significantly among cancer drugs. The essential nuclear enzyme topoisomerase II allows the separation of intertwined DNA strands by creating a transient double stranded break in the DNA backbone. This catalytic cycle of topoisomerase II is believed to be the target of some of the most successful antitumour agents used today, e.g. etoposide (VP-16) in the treatment of testicular and small cell lung cancer (2). There is solid evidence that etoposide, as well as a number of other clinically successful antitumour agents such as daunorubicin and doxorubicin (Adriamycin) (28), are active by inhibiting the resealing of the DNA breaks created by topoisomerase II (19, 21). Although the precise cell killing mechanism is unknown, an obligatory step for the cytotoxicity of the topoisomerase II targeting agents is an increase in cleavable complexes between DNA and topoisomerase II (19). This complex mechanism of cell killing is susceptible to drug modulation.
The clinically active DNA intercalating drug, aclarubicin, completely antagonizes the cytotoxicity of topoisomerase II targeting agents such as etoposide, teniposide, m-AMSA, (amsakrin; 4'-(9-acridinylamino)-methanesulfone-m-anisidide) daunorubicin, and oxaunomycin (15, 16, 17). Not only aclarubicin, but also several other DNA binding agents such as ethidium bromide (24), 9-aminoacridines (7, 20), and chloroquine (18) can antagonize the cytotoxicity of topoisomerase II targeting agents. It is believed that these DNA binding drugs inhibit the initial DNA binding step of the enzyme and thereby suppress the interaction between the enzyme, the topoisomerase II targeting drug, and DNA. Recently, more specific interactions with topoisomerase II have been described. Thus, it appears that cation chelating bis-dioxypiperazines may lock topoisomerase II at its magnesium/ATP binding site at the stage of the catalytic cycle where the homodimeric enzyme is thought to be in the form of a closed bracelet surrounding the DNA (22, 23). By locking the enzyme, the bis-dioxopiperazine seems to hinder topoisomerase II poisons from exerting their cytotoxicity. Thus, the bis-dioxypiperazine derivative ICRF-187 (dexrazoxane; (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane) abolishes both DNA breaks and cytotoxicity caused by the topoisomerase II poisons etoposide and daunorubicin (25).
The antagonistic effect of ICRF-187 has been observed on the drug daunorubicin (14), but not on the chemically very similar doxorubicin, and this latter topoisomerase II poison is therefore excluded from the invention. Similarly no antagonism on clerocidin has been found.